The effect of biologically effective molecules, which are generally pharmaceutical active ingredients, develops mostly both inside and outside biological cells. Hitherto, primarily the problem has occurred that active ingredients whose effect is to develop only inside the cell cause undesired changes in the extracellular space even before passing through the cell membrane. The problem that additionally arises here is that one and the same active ingredient can develop a different effect inside and outside the cell. The actual effect thus comprises two components—the desired intracellular and the undesired extracellular. If the intracellular effect is to be achieved, the extracellular (side-)effect often also had to be accepted—because the transport to the cell generally includes the crossing of an extracellular space.
An equally important problem, but one not hitherto described in the state of the art, is the administration of active ingredients which are supposed to or can develop their effect outside the cell only. Above all in medicine a range of active ingredients is known which not only do not develop the intended effect in the cell but actually have a toxic effect or are harmful in some other way. To this is added the fact that, to achieve a specific extracellular effect, a much higher dose must be administered than is actually required in order to compensate for the “loss” of the active ingredients which have migrated into the inside of the cell.
Active ingredients can act extracellularly on molecules or structures. Such biological molecules of the extracellular space can be for example enzymes, inhibitors, activators or receptors. By “structures” is meant for example the extracellular matrix which is formed from the totality of the macromolecules which are found outside the plasma membrane of cells in tissues and organs.
Important active ingredients in current medical research are effectors which can inhibit inflammatory processes in biological objects, preferably in veterinary and human medicine. Effectors of peptidyl-prolyl-cis/trans-isomerases (PPIases), i.e. PPIase inhibitors, are of particular importance.
While these effectors can differ between the individual PPIase families (Nature Chemical Biology. 3(10):619-29, 2007; Cellular & Molecular Life Sciences. 63(24):2889-900, 2006; Current Topics in Medicinal Chemistry. 3(12):1315-47, 2003; Advances in Protein Chemistry. 59:243-82, 2001), they often have similar inhibiting power compared with sequence-similar family members. Because PPIases within a family can influence very different biochemical reactions, the diagnostic or pharmacological effect of administered active ingredients depends directly on the concentration reached in very different distribution spaces. Thus e.g. some of these PPIase inhibitors (e.g. Biopolymers 84 (2006)125-146; Chemical & Pharmaceutical Bulletin. 54(3):372-376, 2006; Chemistry & Biology. 10(1):15-24, 2003; Nucleic Acids Research. 29(3):767-773, 2001), such as e.g. therapeutically used cyclosporin, are only poorly soluble in water. (DE 19859910). Nevertheless, much higher concentrations are found inside cells after customary medicinal application. It is suspected that the active ingredients pass through the cell membrane and then bind to PPIases intracellularly present. For a cyclosporin derivative (SDZ IMM 125) thus (Anti-Cancer Drugs. 8(4):400-404, 1997; Journal of Pharmacokinetics & Biopharmaceutics. 22(5):327-65, 1994) an approximately 8× higher concentration was able to be detected in blood cells than in the surrounding plasma.
Cyclosporin (also ciclosporin) is a cyclic oligopeptide with an immunosuppressive and calcineurin-inhibiting effect. It is characterized by a selective and reversible immunosuppression mechanism. It selectively blocks the activation of T lymphocytes via the production of specific cytokines which participate in the regulation of these T cells. Above all the synthesis of interleukin-2 is inhibited, whereby simultaneously the proliferation of cytotoxic T lymphocytes which e.g. are responsible for the rejection of foreign tissue is suppressed. Cyclosporin acts intracellularly by binding to the so-called cyclophilines or immunophilines which belong to the family of cyclosporin-binding proteins.
Inhibitors of cyclophilines have a very broad therapeutic spectrum, such as e.g. the treatment of diseases of the respiratory tract, such as e.g. asthma, COPD, pneumonia or emphysema (Expert Opinion on Investigational Drugs 12 (2003), 647-653, Biodrugs 8 (1997) 205-215, American Journal of Respiratory Cell & Molecular Biology 20 (1999), 481-492), metabolic diseases such as diabetes (Transplantation Proceedings 37 (2005), 1857-1860, Molecular Pharmacology 60 (2001), 873-879), inflammatory diseases of the digestive tract (Bone Marrow Transplantation 26 (2000), 545-551, Pharmaceutical Research 20 (2003), 910-917), disorders of the immune system (Immunology Letters 84 (2002), 137-143, Acta Biochimica Polonica 49 (2002), 233-247), inflammations (Journal of Periodontal Research 42 (2007), 580-588, Journal of Neurology, Neurosurgery & Psychiatry 76 (2005), 1115-1120, Transplant Immunology 12 (2004), 151-157), cardiovascular diseases (Journal of Hypertension 17 (1999), 1707-1713, Drug & Chemical Toxicology 21 (1998), 27-34), neurological diseases (Annals of Vascular Surgery 20 (2006), 243-249), diseases associated with a disruption of angiogenesis (Blood Purification 25 (2007), 466-472, International Angiology 24 (2005), 372-379, Nefrologia 23 (2003), 44-48), for the suppression of the immune response in organ transplantation (Bone Marrow Transplantation 38 (2006), 169-174), Biodrugs 14 (2000), 185-193, Clinical Immunotherapeutics 5 (1996), 351-373) and of autoimmune diseases (Immunology & Immunopathology 82(3), 197-202, 1997), arthritic diseases (British Journal of Rheumatology 36 (1997), 808-811, Biodrugs 7 (1997), 376-385), dermatitides (Veterinary Dermatology 17 (2006), 3-16), psoriasis (Journal of Dermatological Treatment 16 (2005), 258-277, Hautarzt 44 (1993), 353-360), in allergies (Cornea 27 (2008), 625, Journal of Small Animal Practice 47 (2006), 434-438, Clinical & Experimental Ophthalmology 34 (2006), 347-353), in multiple sclerosis (Immunopharmacology & Immunotoxicology 21 (1999), 527-549, Journal of Neuroimaging 7 (1997), 1-7), diseases caused by ischemia, such as e.g. infarctions of the heart (Annals of Thoracic Surgery 86 (2008), 1286-1292, Acta Anaesthesiologica Scandinavica 51 (2007), 909-913), of the pancreas (Pancreas 32 (2006), 145-151) or of the brain (Annals of Vascular Surgery 20 (2006), 243-249, Neurological Research 27 (2005), 827-834), kidney diseases, such as e.g. glomerulonephritis (Nephrology Dialysis Transplantation 19 (2004), 3207, Nephron 91 (2002), 509-511), tumours (Journal of Investigative Dermatology 128 (2008), 2467-2473, Endocrinology 148 (2007), 4716-4726), in multiple myelomas (Leukemia 12 (1998), 505-509, Leukemia & Lymphoma 16 (1994), 167-170), in acute or chronic leukaemia (Cancer Chemotherapy & Pharmacology 52 (2003), 449-452, Cancer 97 (2003), 1481-1487), muscular degeneration (Neuroscience Research Communications 31 (2002), 85-92), cachexia (International Journal of Cardiology 85 (2002), 173-183, Drugs 58 (1999), 953-963, 1999), Reiter's Syndrome (Rheumatology 40 (2001), 945-947), bone degradation diseases (European Journal of Pharmacology 564 (2007), 226-231, Biochemical & Biophysical Research Communications 254 (1999), 248-252), in Alzheimer's disease (Biochemical & Biophysical Research Communications 248 (1998), 168-173, Chinese Medical Journal 115 (2002), 884-887), malaria (Molecular & Biochemical Parasitology 99 (1999), 167-181), septic and toxic shock syndrome (Journal of Pharmacology & Experimental Therapeutics 311 (2004), 1256-1263), myalgia (British Journal of Dermatology 147 (2002), 606-607), in a virus infection (Expert Opinion on Emerging Drugs 13 (2008), 393-416), such as e.g. HIV-1, HIV-2, HIV-3 (Journal of Infectious Diseases 194 (2006), 1677-1685, Molecular Medicine Today 1 (1995), 287-291, 1995), cytomegaloviruses (Journal of Virology 81 (2007), 9013-9023) or adenoviruses (Ophthalmologe 105 (2008), 592-594, Ophthalmologe 97 (2000), 764-768) and for promoting hair growth (Archives of Dermatological Research 296(6), 265-269, 2004, Annales de Dermatologie et de Venereologie 127 (2000), 769).
The complex of cyclosporin and cyclophilin then blocks the serine-threonine-phosphatase calcineurin. Its activity state in turn controls the activation of transcription factors such as, say, NF-Kappa B or NFATp/c which play an important role in the activation of various cytokine genes, also including that for interleukin-2. The immunocompetent lymphocytes are hereby arrested during the G0 or G1 phase of the cell cycle, because the proteins essential for cell division such as interleukin-2 can no longer be produced. T helper cells which increase the activity of the cytotoxic T cells responsible for rejection are the preferred point of attachment for cyclosporin.
In addition cyclosporin inhibits the synthesis and release of further lymphokines which are responsible for the proliferation of mature cytotoxic T lymphocytes and for further functions of the lymphocytes. The ability of cyclosporin to block interleukin-2 is critical for its clinical effectiveness: Transplant recipients who display a good tolerance of their transplants are characterized by a low production of interleukin-2. Conversely, in patients with a manifest rejection reaction, no inhibition of interleukin-2 production can be established.